Myeloproliferative disorders (MPDs) are a group of conditions characterized by chronic increases in some or all of the blood cells. Recently, we and others have identified a mutation in the JAK2 tyrosine kinases in classic MPDs including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The mutant enzyme designated JAK2V617F possesses deregulated and enhanced kinase activity and induces constitutive activation of downstream signaling events in transfected cells. We have now generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The transgenic mice displayed marked increases in blood counts and developed phenotypes that closely resembled human ET and PV in a transgene dose- dependent manner. The mice also developed PMF-like symptoms as they aged. Our data provides unequivocal evidence that JAK2V617F can cause MPDs and that the phenotypes are determined by the expression level of the mutant enzyme. Furthermore, by generating JAK2 transgenic mice and crossing them with JAK2V617F transgenic mice, we have found that over- expression of wild type JAK2 is not only non-pathogenic but also totally suppresses the pathogenic function of JAK2V617F, suggesting that wild type JAK2 antagonizes mutant JAK2V617F. These transgenic mouse models provide an invaluable tool to study MPDs and normal hematopoiesis. In this study, we will utilize these tools to reveal the pathological role of JAK2V617F, the molecular and cellular mechanism on which MPDs develop, and the interplay of mutant JAK2V617F with wild type JAK2. Specifically, we will fully characterize the phenotypes of JAK2V617F transgenic mice and reveal the dose-dependent nature of JAK2V617F-induced MPD phenotypes. We will thoroughly investigate the effects of JAK2V617F on the proliferation, differentiation, and survival of hematopoietic stem/progenitor cells by using various in vitro cell culture methods and in vivo stem cell transplant techniques and analyze the activation of various signaling pathways in these cells. This study will provide novel insight into the mechanism by which abnormal hematopoiesis arises in MPD patients and normal hematopoiesis is regulated under healthy conditions. It addresses how JAK2V617F causes MPDs and answers the question why a single point mutation causes so many phenotypes. This study should have major implications in development of therapeutic drugs and procedures to treat MPDs in the future.